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Hervas et al. J Transl Genet Genom 2021;5:278-87 https://dx.doi.org/10.20517/jtgg.2021.25 Page 284

taken together, suggest that genetic variation in BDNF contributes to adverse reactions rather than to the
efficacy of pharmacological treatment in ASD subjects. However, the possible role of these genetic variants
on BDNF plasma levels and their contribution to treatment side effects need further investigation.

COMT is one of the main enzymes involved in the degradation of catecholamines including dopamine,
epinephrine, and norepinephrine, whose pathways are targeted by methylphenidate and other
psychotropics. The COMT rs4680(Val158Met) polymorphism has been associated with methylphenidate
response in children and adolescents with ADHD [19,48-50] and children with ASD . Furthermore, the level of
[14]
[48]
irritability was predicted by COMT variants in children with ADHD treated with methylphenidate . The
COMT rs4680 variant was not associated with treatment response in our sample, but was marginally
associated with presence of side effects, with rs4680-G/G (Val/Val) individuals presenting more lasting side
effects (P = 0.02) and BMI (P = 0.04) in the study cohort.

In summary, we observed several associations between the candidate genes analysed and clinical outcome in
patients with ASD treated with a variety of psychotropics. A SLC6A3 genetic variant predicted response to
methylphenidate in our ASD cohort, whereas HTR2A and HTR2C allele and haplotype distributions were
mainly associated with adverse reactions such as somnolence, mood alterations, and BMI. ANKK1, COMT,
and BDNF genetic variants were mainly associated with treatment side effects. These associations resembled
those observed in other pathologies, suggesting a similar mechanism of action in ASD and/or confirming
the common origin of the symptoms treated.

Our study has several limitations. None of the findings reported in this study survived multiple analyses
corrections, considering the number of polymorphisms and phenotypes analysed. Our findings require
confirmation in independent studies. The study sample size is moderate, which may have affected the
statistical significance of the findings and produced false positives or negatives. However, it is one of the
largest cohorts collated for ASD pharmacogenetic studies. Furthermore, most of our findings coincide with
the pharmacogenetic results observed in other pathologies, suggesting they are true findings. Another
limitation is that we did not investigate functional variants in drug metabolising hepatic enzymes. Although
there is extensive evidence on the influence on functional variants in cytochrome P450 (CYP) metabolic
enzymes on treatment response, the main drug used in our study cohort, methylphenidate, is metabolised
mainly by CES1. Inconsistent results on the genetic influence of CES1 variants on treatment response have
been reported [51,52] . However, reports of associations between genetic variants in CYP enzymes and response
to psychotropic treatment in children with schizophrenia or ASD merit further investigation in independent
studies [2,53] .

In conclusion, our study showed that genetic variation in dopamine (SLCA3) and serotonin (HTR2A and
HTR2C) may influence response to psychotropic treatment in patients with ASD and side effects, whereas
ANKK1, COMT, and BDNF polymorphisms may contribute to adverse reactions. Associations between the
SLC6A3 and methylphenidate response have been reported in other pathologies and may constitute a useful
biomarker for the selection of adequate treatment. The genetic associations with adverse reactions may help
to predict or prevent the development of side effects, although their value to discriminate between
treatments is unclear. Nevertheless, if confirmed these genetic variants may be used as predictors of clinical
outcome and help to personalise pharmacological treatments in patients with ASD.

DECLARATIONS
Authors’ contributions
Study design, sample recruitment, data analyses, results interpretation, and paper writing: Hervas A